Pulmonary medicine is facing a broad spectrum of unmet clinical needs, mainly for three reasons: (1) Lack of regional and quantitative information about lung function especially in obstructive disease;(2) Lack of a radiation-free diagnostic modality in pediatric lung diseases to initiate treatment at the right time;(3) Lack of a grading scale for inflammatory activity and diffusion barriers in interstitial lung disease. The availability of a safe, affordable, and highly quantitative modality for 3-D imaging of lung function would improve early diagnosis and discrimination of diseases, accelerate testing of therapies by pharmaceutical companies, and assist in personalized disease management and intervention decisions for children and adult patients. Hyperpolarized xenon (HXe) MRI is a leading candidate to address this need. Since the depolarization of HXe atoms in lungs is dominated by the presence of paramagnetic oxygen gas molecules, an imaging sequence that determines the rate of signal loss can be interpreted as a map of the local alveolar oxygen concentration. Our recent hundred-fold improvements in HXe production technology deliver high polarizations of HXe in multi-liter quantities. We have incorporated this technology into a compact platform, delivered it to clinical partners, and operated it remotely over periods of several months. Our xenon-tuned 32-element parallel receive coil with integrated asymmetric birdcage transmit coil achieves highly uniform flip angles with maximal speed-up factors, allowing several 3D images in a single breath hold. Our Phase I project demonstrated feasibility for a robust, quantitative, high resolution protocol by implementing and performing pulse sequences that determine the rate of signal loss of pulmonary HXe, applying novel image registration techniques, and estimating corrections due to loss of HXe into the bloodstream. In this Phase 2 project we propose to establish HXe mapping of local alveolar oxygen as a clinically validated and commercially viable diagnostic protocol. We will implement imaging sequences that reconstruct oxygen-induced signal loss with three state-of-the-art acceleration schemes to compare their resolution, SNR, susceptibility to artifacts, and biomarker accuracy. We will compare these sequences against three truth standards: precisely mixed bags of gas, healthy volunteers performing tidal breathing with their exhaled gases calibrated with gas concentration analysis, and hyperventilated healthy volunteers with exhaled gases calibrated with gas concentration analysis. Comparing measurements after tidal breathing to others after hyperventilating will allow calibration and improvement of our models correcting for <10% xenon signal lost to the bloodstream. Finally we will explore and demonstrate the utility of this protocol in the diagnosis and severity staging of several patients with COPD (ventilation abnormalities), interstitial disease (gas exchange abnormalities), and sickle cell disease (perfusion abnormalities). The US FDA has approved our hyperpolarized xenon for Phase 2 trials in subjects with lung disease. PUBLIC HEALTH RELEVANCE: Pulmonary functional magnetic resonance imaging with hyperpolarized xenon, a technology which recently improved by two orders of magnitude, has the potential to address unmet needs in managing a full range of lung diseases, including COPD, asthma, cystic fibrosis, and interstitial diseases. We propose to develop an innovative, robust, and quantitative probe of regional alveolar oxygen concentration with high resolution in three-dimensions and validate it against truth standards. This non-ionizing, well-tolerated, quick, and affordable imaging modality would provide pulmonologists caring for children through adult patients with maps of the highest measure of lung function: regional oxygen exchange into the bloodstream.